.alpha.-1-Antichymotrypsin is a serine protease inhibitor (serpin). In its native, circulating form, it is a glycoprotein of between 55,000 and 66,000 daltons, with the variation attributed to microheterogeneity in glycosylation. It is synthesized predominantly in the liver, and has also been reported in mast cells, sinus histiocytes, endothelial cells, and in cells of the histio/monocytic line. In response to inflammatory stimuli, plasma levels of .alpha.-1-antichymotrypsin increase more than four-fold within several hours.
The precise biological role of .alpha.-1-antichymotrypsin has not been determined. Based on its rapid rate of association with cathepsin G, it may regulate the activity of this neutrophil serine protease. However, other targets are also possible. Chymotrypsin-like enzymes and their inhibitors have been identified in a wide variety of normal and abnormal biological processes including: modulation of cellular functions, DNA binding, inhibition of certain parasite functions and processing of vasoconstrictor proteins. .alpha.-1-antichymotrypsin appears to be a component of the amyloid deposit in Alzheimer's plaques and is present in various carcinomas and in some tissues of the reproductive system.
Human .alpha.-1-antichymotrypsin forms SDS-stable complexes with its target enzymes, which is a general property of serpin/serine protease interactions. Little of a detailed nature is known about the nature of these complexes. Although high-resolution crystal structures of chymotrypsin and chymotrypsin/small molecular inhibitor complexes have been solved and NMR analysis of the enzyme have been reported, no direct structural studies of human .alpha.1-antichymotrypsin alone or as a complex with a serine protease have been reported.
Antithrombin III and .alpha.-1-antitrypsin are also serine protease inhibitors. Antithrombin III inactivates thrombin by forming an irreversible complex with it. Antithrombin III also inhibits clotting factors IX.sub.a, X.sub.a and XI.sub.a. .alpha.-1-antitrypsin inhibits tyrpsin by binding to its active site, and neutralizes any trypsin formed prematurely within the pancreatic cells or pancreatic ducts.
There is evidence that proteases and oxidants play a central role in establishing and maintaining shock physiology, and that protease inhibitors can favorably modify the outcome of shock. Small molecule protease inhibitors have been shown to have efficacy in pancreatitis in humans. Similarly, antichymotrypsins may be implicated in treatment of coagulation disorders as in liver diseases. Proteases are also important mediators of inflammatory diseases. Regulation of these enzymes by their inhibitors are critical for the control of tissue destruction in these diseases.
Despite the availability of human .alpha.-1-antichymotrypsin from serum, quantities large enough for therapeutic uses have been unobtainable, due in large part to the limited availability of human serum. Consequently, there is a great need for other sources of .alpha.-1-antichymotrypsin to fill the needs created by therapeutic uses.